Clinical Trials List
Protocol NumberJS001-035-III-HCC
2020-06-30 - 2024-10-11
Phase III
Recruiting3
A randomized, open-label, multi-center phase III clinical study to evaluate the safety and efficacy of Toripalimab (JS001) combined with Bevacizumab versus Sorafenib as first-line therapy for advanced hepatocellular carcinoma (HCC)
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Trial Applicant
PROTECH PHARMASERVICES CORPORATION
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Sponsor
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Trial scale
Multi-Regional Multi-Center
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Update
2025/08/20
Investigators and Locations
The Actual Total Number of Participants Enrolled
0 Recruiting
The Actual Total Number of Participants Enrolled
0 Recruiting
Co-Principal Investigator
- Zu-Yau Lin Digestive System Department
- Chia-Yen Dai Digestive System Department
- Ming-Lung Yu Digestive System Department
- Wan-Long Chuang Digestive System Department
- Chung-Feng Huang Digestive System Department
- Shinn-Cherng Chen Digestive System Department
- 黃駿逸 Digestive System Department
The Actual Total Number of Participants Enrolled
0 Recruiting
Condition/Disease
To verify the efficacy of Toripalimab combined with Bevacizumab as the firstline therapy for advanced hepatocellular carcinoma (HCC).
Objectives
Primary objective:
To verify the efficacy of Toripalimab combined with Bevacizumab as the firstline therapy for advanced hepatocellular carcinoma (HCC).
Secondary objectives：
> To evaluate the safety of Toripalimab combined with Bevacizumab as the first-line therapy for patients with advanced HCC;
Test Drug
Toripalimab (JS001)
Active Ingredient
Toripalimab (JS001)
Dosage Form
Dosage
240 mg/6 mL/vial
Endpoints
Primary study endpoints:
> Progression-free survival (PFS) evaluated by the Independent Imaging Review Committee (IRC) per RECIST v1.1;
> Overall survival (OS);
Secondary study endpoints:
Efficacy:
> Objective response rate (ORR), disease control rate (DCR), time to progression (TTP), and duration of response (DOR) evaluated by the IRC
according to RECIST v1.1 criteria;
> Objective response rate (ORR), disease control rate (DCR), time to progression (TTP) , duration of response (DOR) and progression-free survival (PFS) evaluated by the IRC according to imRECIST;
> ORR, DCR, TTP, DOR, and PFS evaluated by the investigators according to RECIST v1.1 and immune-modified response evaluation criteria in solid tumors (imRECIST) criteria;
> PFS rates at 6 months and 1 year of both groups (RECIST v1.1 and imRECIST criteria);
> OS rates at 1 and 2 years of both groups.
Safety:
> Incidence, severity, and outcome of adverse events (AEs) and serious adverse events (SAEs) evaluated according to national cancer institute - standard for common terminology for adverse events (NCI-CTC AE) v5.0; and occurrence of immune-related AEs.
> Changes in vital signs, physical examination, electrocardiogram, and laboratory tests from baseline.
Others:
> Immunogenicity of Toripalimab in advanced HCC patients;
> Correlation between related biomarkers, including the expression of PD-L1 and TMB, and the effect of combined therapy.
> Progression-free survival (PFS) evaluated by the Independent Imaging Review Committee (IRC) per RECIST v1.1;
> Overall survival (OS);
Secondary study endpoints:
Efficacy:
> Objective response rate (ORR), disease control rate (DCR), time to progression (TTP), and duration of response (DOR) evaluated by the IRC
according to RECIST v1.1 criteria;
> Objective response rate (ORR), disease control rate (DCR), time to progression (TTP) , duration of response (DOR) and progression-free survival (PFS) evaluated by the IRC according to imRECIST;
> ORR, DCR, TTP, DOR, and PFS evaluated by the investigators according to RECIST v1.1 and immune-modified response evaluation criteria in solid tumors (imRECIST) criteria;
> PFS rates at 6 months and 1 year of both groups (RECIST v1.1 and imRECIST criteria);
> OS rates at 1 and 2 years of both groups.
Safety:
> Incidence, severity, and outcome of adverse events (AEs) and serious adverse events (SAEs) evaluated according to national cancer institute - standard for common terminology for adverse events (NCI-CTC AE) v5.0; and occurrence of immune-related AEs.
> Changes in vital signs, physical examination, electrocardiogram, and laboratory tests from baseline.
Others:
> Immunogenicity of Toripalimab in advanced HCC patients;
> Correlation between related biomarkers, including the expression of PD-L1 and TMB, and the effect of combined therapy.
Inclution Criteria
Patients meeting all the following inclusion criteria can be enrolled in this study:
1. Age of 18-75 years (inclusive), male or female.
2. Histological or cytological diagnosis of HCC or clinical diagnosis of HCC in cirrhotic patients per the American Association for the Study of Liver Diseases (AASLD) guideline.
3. Barcelona Clinic Liver Cancer (BCLC) stage Category B (intermediate stage) or C (adavanced stage), and unsuitable for radical surgical and/or local therapy, or has progressed following surgical and/or local therapy.
4. No previous systemic therapy for HCC, mainly including systemic chemotherapy, anti-angiogenic drugs or other molecular targeted therapy, immunotherapy containing CTLA-4, PD-1/PD-L1 monoclonal antibody) for HCC.
5. Having ≥ 1 measurable lesion per RECISTv1.1. Requirement: the selected target lesion has not been treated locally before, or is located in the area of previous local therapy, but determined as PD through radiological examination.
6. Child-Pugh class A, with no history of hepatic encephalopathy.
7. Eastern Cooperative Oncology Group Performance Status (ECOG PS) status of 0 or 1.
8. Predicted life expectancy ≥ 12 weeks.
9. Main organ function meets the following requirements: no blood transfusion within 14 days prior to screening, no use of hematopoietic stimulating factor (including G-CSF, GM-CSF, EPO and TPO) or infusion of human albumin preparation.
> Absolute neutrophil count ≥1.5×109/L;
> Platelet count ≥ 75×109/L;
> Haemoglobin ≥ 90 g/L;
> Serum albumin ≥ 29 g/L;
> Serum total bilirubin ≤1.5 × upper limit of normal (ULN); Alanine aminotransferase (ALT), aspartate aminotransferase (AST) ≤ 5×ULN;
> Serum creatinine (Cr) ≤1.5×ULN or Cr clearance ≥50 mL/min (calculated by Cockcroft-Gault formula);
> International normalized ratio (INR) ≤ 2 or exceeding of prothrombin time (PT) to upper limit of normal ≤ 6 seconds;
> Urine protein < 2+ (If urine protein≥ 2+, 24h urine protein quantification should be performed, the subjects with 24h urine protein quantification <1.0g can be enrolled).
10. In case of HBsAg (+) and/or HBcAb (+), HBV DNA is required to be < 500 IU/mL, (the enrollment will be determined upon discussion with the sponsor in accordance with specific condition, if the lower limit of minimum measurable value is higher than 500IU/mL at local site) and it is required to continue the effective anti-HBV therapy that has been adopted in the full course, or start to use entecavir or tenofovir after screening in the full course
during the study; Patients with anti-HCV antibody positive and HCVRNA>103 copies/mL will be excluded; HBV/HCV co-infected patients, i.e., positive for both HbsAg and HCV-RNA, will be excluded.
11. Female subjects of childbearing potential must receive serum pregnancy test within 7 days before randomization and the result should be negative, and should be willing to adopt reliable and effective contraceptive methods during the trial and within 60 days after the last dose of study drug. The male patients whose partners are women of childbearing potential must agree to use reliable and effective contraceptive methods during the trial and within 60 days after the last dose of study drug.
12. Being voluntary to participate in the study, sufficiently informed consent and signature of written informed consent form, with good compliance.
1. Age of 18-75 years (inclusive), male or female.
2. Histological or cytological diagnosis of HCC or clinical diagnosis of HCC in cirrhotic patients per the American Association for the Study of Liver Diseases (AASLD) guideline.
3. Barcelona Clinic Liver Cancer (BCLC) stage Category B (intermediate stage) or C (adavanced stage), and unsuitable for radical surgical and/or local therapy, or has progressed following surgical and/or local therapy.
4. No previous systemic therapy for HCC, mainly including systemic chemotherapy, anti-angiogenic drugs or other molecular targeted therapy, immunotherapy containing CTLA-4, PD-1/PD-L1 monoclonal antibody) for HCC.
5. Having ≥ 1 measurable lesion per RECISTv1.1. Requirement: the selected target lesion has not been treated locally before, or is located in the area of previous local therapy, but determined as PD through radiological examination.
6. Child-Pugh class A, with no history of hepatic encephalopathy.
7. Eastern Cooperative Oncology Group Performance Status (ECOG PS) status of 0 or 1.
8. Predicted life expectancy ≥ 12 weeks.
9. Main organ function meets the following requirements: no blood transfusion within 14 days prior to screening, no use of hematopoietic stimulating factor (including G-CSF, GM-CSF, EPO and TPO) or infusion of human albumin preparation.
> Absolute neutrophil count ≥1.5×109/L;
> Platelet count ≥ 75×109/L;
> Haemoglobin ≥ 90 g/L;
> Serum albumin ≥ 29 g/L;
> Serum total bilirubin ≤1.5 × upper limit of normal (ULN); Alanine aminotransferase (ALT), aspartate aminotransferase (AST) ≤ 5×ULN;
> Serum creatinine (Cr) ≤1.5×ULN or Cr clearance ≥50 mL/min (calculated by Cockcroft-Gault formula);
> International normalized ratio (INR) ≤ 2 or exceeding of prothrombin time (PT) to upper limit of normal ≤ 6 seconds;
> Urine protein < 2+ (If urine protein≥ 2+, 24h urine protein quantification should be performed, the subjects with 24h urine protein quantification <1.0g can be enrolled).
10. In case of HBsAg (+) and/or HBcAb (+), HBV DNA is required to be < 500 IU/mL, (the enrollment will be determined upon discussion with the sponsor in accordance with specific condition, if the lower limit of minimum measurable value is higher than 500IU/mL at local site) and it is required to continue the effective anti-HBV therapy that has been adopted in the full course, or start to use entecavir or tenofovir after screening in the full course
during the study; Patients with anti-HCV antibody positive and HCVRNA>103 copies/mL will be excluded; HBV/HCV co-infected patients, i.e., positive for both HbsAg and HCV-RNA, will be excluded.
11. Female subjects of childbearing potential must receive serum pregnancy test within 7 days before randomization and the result should be negative, and should be willing to adopt reliable and effective contraceptive methods during the trial and within 60 days after the last dose of study drug. The male patients whose partners are women of childbearing potential must agree to use reliable and effective contraceptive methods during the trial and within 60 days after the last dose of study drug.
12. Being voluntary to participate in the study, sufficiently informed consent and signature of written informed consent form, with good compliance.
Exclusion Criteria
Patients can not be enrolled in the study if any one of the following criteria is fulfilled:
1. Known cholangiocellular carcinoma (ICC) or mixed cell carcinoma, sarcomatoid HCC and hepatic fibrolamellar carcinoma.
2. History of malignancy other than HCC within 5 years prior to screening, with the exception of cured localized malignancies including cervical carcinoma in situ, skin basal cell carcinoma and carcinoma in situ of prostate.
3. Hepatic surgery and/or local therapy or investigational treatment with for HCC within 4 weeks prior to randomization, or palliative radiotherapy for bone metastatic lesion within 2 weeks prior to randomization, or Chinese medicine preparation with anti-liver cancer effect within 2 weeks prior to randomization, and non-recovery (not recovered to ≤ NCI-CTCAE v5.0
grade 1) from side effects of any such treatment (except alopecia).
4. Prior other anti-PD-1 antibody therapy or other immunotherapy against PD1 / PD-L1.
5. Uncontrolled pericardial effusion, uncontrolled pleural effusion or clinically obvious moderate/severe pleural effusion at screening, defined as reaching the following criteria: having clinical symptoms and physical examination identifies pleural effusion; Paracentesis and/or intracavitary administration are required for pleural effusion during screening.
6. History of gastrointestinal hemorrhage within 6 months prior to randomization; the patients with portal hypertension need to receive gastroscopy to exclude the patients with “red sign”, if they are considered by investigators to have high risk for hemorrhage (including moderate-to-severe esophageal and/or gastric varices with hemorrhagic risk, locally active peptic ulcer and persistent fecal occult blood (+)). The patient needs to be excluded if there is a history of “red sign” in gastroscopy.
7. Having ≥ grade 3 (NCI-CTC AE v5.0) gastrointestinal or nongastrointestinal fistula at present.
8. Cancer thrombus in the main trunk of portal vein involving contralateral portal vein branch, or involving superior mesenteric vein. Cancer thrombus in inferior vena cava should be excluded.
9. Serious cardiovascular and cerebrovascular diseases:
> New York Heart Association (NYHA) grade II congestive heart failure, unstable angina pectoris, myocardial infarction or cerebrovascular accidental stroke or poorly controlled arrhythmia within 12 months prior to randomization.
> Left ventricular ejection fraction (LVEF) <50% in color Doppler echocardiography.
> Corrected QT interval (QTc) >480ms (calculated using Fridericia method, in case of abnormal QTc, the test may be performed 3 times continuously at 2-minute interval and apply the average value).
> Hypertension that can not be controlled by drug (systolic blood pressure (BP) ≥150 mmHg and/or diastolic blood pressure ≥100mmHg).
> Previous occurrence of hypertensive crisis or hypertensive encephalopathy.
10. Having major bleeding and coagulation disorders or other obvious evidence on hemorrhagic tendency:
> Clinically significant hemoptysis or tumor hemorrhage for any reason within 2 weeks prior to randomization;
> Thrombosis or embolic event within 6 months prior to randomization;
> Use of anticoagulation therapy for therapeutic purpose within 2 weeks prior to randomization (except low molecular weight heparin);
> Requiring antiplatelet therapy;
> Current or recent (within 10 days prior to randomization) use of aspirin (> 325 mg/d), clopidogrel (> 75 mg/d), or dipyridamole, ticlopidine, and cilostazol;
> Metastatic disease that involves blood vessels, or major airways, or centrally located mediastinal tumor masses of large volume, with significant risks of bleeding.
11. Medium to large surgical treatment within 4 weeks prior to randomization (except diagnostic biopsy).
12. Central nervous system metastases.
13. Serious, non-healing or dehiscing wound, active ulcer or untreated bone fracture.
14. Vaccination of live vaccine within 30 days prior to randomization.
15. Active autoimmune diseases requiring systemic treatment (i.e., immunomodulatory drug, corticosteroid or immunosuppressant) in the past 2 years; however, replacement therapy (e.g., thyroxine, insulin or physiological corticosteroid replacement therapy for renal or pituitary insufficiency), inhaled or topical corticosteroids will not be excluded.
16. History of clear interstitial lung disease or non-infectious pneumonia, unless induced by local radiotherapy, or history of active tuberculosis.
17. Any serious acute and chronic infection requiring systemic antibacterial, antifungal or antiviral therapy at screening, not including viral hepatitis.
18. Known history of human immunodeficiency virus (HIV) infection.
19. Previously receiving allogeneic stem cell or solid organ transplantation.
20. Inability to swallow tablets, malabsorption syndrome or any condition that affects gastrointestinal absorption.
21. Known history of serious allergy to any monoclonal antibody, targeted antiangiogenic drug.
22. Other unsuitable subjects as per the investigators.
1. Known cholangiocellular carcinoma (ICC) or mixed cell carcinoma, sarcomatoid HCC and hepatic fibrolamellar carcinoma.
2. History of malignancy other than HCC within 5 years prior to screening, with the exception of cured localized malignancies including cervical carcinoma in situ, skin basal cell carcinoma and carcinoma in situ of prostate.
3. Hepatic surgery and/or local therapy or investigational treatment with for HCC within 4 weeks prior to randomization, or palliative radiotherapy for bone metastatic lesion within 2 weeks prior to randomization, or Chinese medicine preparation with anti-liver cancer effect within 2 weeks prior to randomization, and non-recovery (not recovered to ≤ NCI-CTCAE v5.0
grade 1) from side effects of any such treatment (except alopecia).
4. Prior other anti-PD-1 antibody therapy or other immunotherapy against PD1 / PD-L1.
5. Uncontrolled pericardial effusion, uncontrolled pleural effusion or clinically obvious moderate/severe pleural effusion at screening, defined as reaching the following criteria: having clinical symptoms and physical examination identifies pleural effusion; Paracentesis and/or intracavitary administration are required for pleural effusion during screening.
6. History of gastrointestinal hemorrhage within 6 months prior to randomization; the patients with portal hypertension need to receive gastroscopy to exclude the patients with “red sign”, if they are considered by investigators to have high risk for hemorrhage (including moderate-to-severe esophageal and/or gastric varices with hemorrhagic risk, locally active peptic ulcer and persistent fecal occult blood (+)). The patient needs to be excluded if there is a history of “red sign” in gastroscopy.
7. Having ≥ grade 3 (NCI-CTC AE v5.0) gastrointestinal or nongastrointestinal fistula at present.
8. Cancer thrombus in the main trunk of portal vein involving contralateral portal vein branch, or involving superior mesenteric vein. Cancer thrombus in inferior vena cava should be excluded.
9. Serious cardiovascular and cerebrovascular diseases:
> New York Heart Association (NYHA) grade II congestive heart failure, unstable angina pectoris, myocardial infarction or cerebrovascular accidental stroke or poorly controlled arrhythmia within 12 months prior to randomization.
> Left ventricular ejection fraction (LVEF) <50% in color Doppler echocardiography.
> Corrected QT interval (QTc) >480ms (calculated using Fridericia method, in case of abnormal QTc, the test may be performed 3 times continuously at 2-minute interval and apply the average value).
> Hypertension that can not be controlled by drug (systolic blood pressure (BP) ≥150 mmHg and/or diastolic blood pressure ≥100mmHg).
> Previous occurrence of hypertensive crisis or hypertensive encephalopathy.
10. Having major bleeding and coagulation disorders or other obvious evidence on hemorrhagic tendency:
> Clinically significant hemoptysis or tumor hemorrhage for any reason within 2 weeks prior to randomization;
> Thrombosis or embolic event within 6 months prior to randomization;
> Use of anticoagulation therapy for therapeutic purpose within 2 weeks prior to randomization (except low molecular weight heparin);
> Requiring antiplatelet therapy;
> Current or recent (within 10 days prior to randomization) use of aspirin (> 325 mg/d), clopidogrel (> 75 mg/d), or dipyridamole, ticlopidine, and cilostazol;
> Metastatic disease that involves blood vessels, or major airways, or centrally located mediastinal tumor masses of large volume, with significant risks of bleeding.
11. Medium to large surgical treatment within 4 weeks prior to randomization (except diagnostic biopsy).
12. Central nervous system metastases.
13. Serious, non-healing or dehiscing wound, active ulcer or untreated bone fracture.
14. Vaccination of live vaccine within 30 days prior to randomization.
15. Active autoimmune diseases requiring systemic treatment (i.e., immunomodulatory drug, corticosteroid or immunosuppressant) in the past 2 years; however, replacement therapy (e.g., thyroxine, insulin or physiological corticosteroid replacement therapy for renal or pituitary insufficiency), inhaled or topical corticosteroids will not be excluded.
16. History of clear interstitial lung disease or non-infectious pneumonia, unless induced by local radiotherapy, or history of active tuberculosis.
17. Any serious acute and chronic infection requiring systemic antibacterial, antifungal or antiviral therapy at screening, not including viral hepatitis.
18. Known history of human immunodeficiency virus (HIV) infection.
19. Previously receiving allogeneic stem cell or solid organ transplantation.
20. Inability to swallow tablets, malabsorption syndrome or any condition that affects gastrointestinal absorption.
21. Known history of serious allergy to any monoclonal antibody, targeted antiangiogenic drug.
22. Other unsuitable subjects as per the investigators.
The Estimated Number of Participants
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Taiwan
30 participants
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Global
280 participants
